3-191375291-A-G

Position:

• chr3-191375291-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_178335.3(CCDC50):​c.678A>G​(p.Lys226Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0982 in 1,613,458 control chromosomes in the GnomAD database, including 12,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (4038 hom., cov: 32)
  • Exomes 𝑓: 0.090 (8790 hom.)
• Consequence: CCDC50 NM_178335.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.614

Genes affected

CCDC50 (HGNC:18111): (coiled-coil domain containing 50) This gene encodes a soluble, cytoplasmic, tyrosine-phosphorylated protein with multiple ubiquitin-interacting domains. Mutations in this gene cause nonsyndromic, postlingual, progressive sensorineural DFNA44 hearing loss. In mouse, the protein is expressed in the inner ear during development and postnatal maturation and associates with microtubule-based structures. This protein may also function as a negative regulator of NF-kB signaling and as an effector of epidermal growth factor (EGF)-mediated cell signaling. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Oct 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 3-191375291-A-G is Benign according to our data. Variant chr3-191375291-A-G is described in ClinVar as [Benign]. Clinvar id is 48157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-191375291-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.614 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC50	NM_178335.3	c.678A>G	p.Lys226Lys	synonymous_variant	6/12	ENST00000392455.9	NP_848018.1
CCDC50	XM_011512460.2	c.678A>G	p.Lys226Lys	synonymous_variant	6/8		XP_011510762.1
CCDC50	NM_174908.4	c.449-4868A>G		intron_variant			NP_777568.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC50	ENST00000392455.9	c.678A>G	p.Lys226Lys	synonymous_variant	6/12	1	NM_178335.3	ENSP00000376249.4
CCDC50	ENST00000392456.4	c.449-4868A>G		intron_variant		1		ENSP00000376250.4

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27071 AN: 152014 Hom.: 4033 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.0274

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.0930

Gnomad EAS AF: 0.213

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0393

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.0727

Gnomad OTH AF: 0.148

GnomAD3 exomes AF: 0.123 AC: 30769 AN: 249834 Hom.: 2848 AF XY: 0.114 AC XY: 15423 AN XY: 135028

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.173

Gnomad ASJ exome AF: 0.0958

Gnomad EAS exome AF: 0.209

Gnomad SAS exome AF: 0.118

Gnomad FIN exome AF: 0.0444

Gnomad NFE exome AF: 0.0733

Gnomad OTH exome AF: 0.105

GnomAD4 exome AF: 0.0898 AC: 131291 AN: 1461326 Hom.: 8790 Cov.: 58 AF XY: 0.0889 AC XY: 64594 AN XY: 726970

Gnomad4 AFR exome AF: 0.416

Gnomad4 AMR exome AF: 0.170

Gnomad4 ASJ exome AF: 0.0941

Gnomad4 EAS exome AF: 0.212

Gnomad4 SAS exome AF: 0.118

Gnomad4 FIN exome AF: 0.0430

Gnomad4 NFE exome AF: 0.0711

Gnomad4 OTH exome AF: 0.109

GnomAD4 genome AF: 0.178 AC: 27097 AN: 152132 Hom.: 4038 Cov.: 32 AF XY: 0.174 AC XY: 12974 AN XY: 74382

Gnomad4 AFR AF: 0.407

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.0930

Gnomad4 EAS AF: 0.213

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0393

Gnomad4 NFE AF: 0.0726

Gnomad4 OTH AF: 0.146

Alfa AF: 0.0971 Hom.: 1896

Bravo AF: 0.196

Asia WGS AF: 0.163 AC: 567 AN: 3478

EpiCase AF: 0.0763

EpiControl AF: 0.0768

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Lys226Lys in Exon 06 of CCDC50: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, and has been identified in 39.2% (1467/3738) o f African American chromosomes from a broad population by the NHLBI Exome Sequen cing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2028573). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.38
DANN	Benign	0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2028573; hg19: chr3-191093080; COSMIC: COSV66668040;